In order to prevent central nervous system injury in the newborn from hyperbilirubinemia, the mechanisms responsible for physiologic jaundice in the neonate must be more fully understood. Studies in newborn rhesus monkeys in this laboratory during the first three weeks of life have demonstrated a complex series of interacting factors which lead to retention of unconjugated bilirubin. These factors include increased bilirubin load presented to the liver, decreased hepatic uptake of bilirubin, decreased hepatic conjugation of bilirubin and decreased hepatic excretion of bilirubin. Two phases of hyperbilirubinemia have also been observed. Phase I, lasting 48 hours and beginning at birth, is characterized by a rapid rise with a peak at 24 hours and an equally rapid decline by 48 hours of life. Defective conjugation of bilirubin is primarily responsible for Phase I hyperbilirubinemia in combination with increased bilirubin load of from 4 to 10 fold as compared with the adult rhesus. Phase II begins at 48 hours and lasts for approximately 5 days and is characterized by a low grade hyperbilirubinemia of 1.0 mg%. This low grade hyperbilirubinemia is believed to result from relative deficiency in hepatic uptake of bilirubin combined with the persisting marked increase in hepatic bilirubin load. The proposed studies will further elucidate the mechanisms responsible for the increased bilirubin load and its sources and will define more clearly the defect in hepatic uptake of bilirubin during Phase II. Further studies of plasma protein binding of bilirubin using various techniques including new dye binding studies will also be conducted.